LAMIVUDINE; STAVUDINE
Clinical safety rating: safe
Other drugs that cause peripheral neuropathy or pancreatitis increase risk Can cause peripheral neuropathy and pancreatitis.
Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) that inhibits HIV-1 reverse transcriptase via DNA chain termination after intracellular phosphorylation to lamivudine triphosphate. Stavudine is also an NRTI that inhibits HIV-1 reverse transcriptase after phosphorylation to stavudine triphosphate.
| Metabolism | Lamivudine is primarily eliminated renally as unchanged drug; minor hepatic metabolism (<10%). Stavudine is eliminated renally as unchanged drug; no significant metabolism by CYP450 enzymes. |
| Excretion | Lamivudine: 70% renal excretion via glomerular filtration and active tubular secretion as unchanged drug; 5-10% fecal. Stavudine: 40% renal excretion via glomerular filtration and active tubular secretion; 34-39% unchanged in urine; fecal excretion minimal. |
| Half-life | Lamivudine: 5-7 hours in adults; prolonged to 19-28 hours in severe renal impairment (CrCl <10 mL/min). Stavudine: 1.0-1.6 hours; prolonged to 7.4-8.2 hours in severe renal impairment. |
| Protein binding | Lamivudine: <36% bound to plasma albumin. Stavudine: <1% bound to plasma proteins. |
| Volume of Distribution | Lamivudine: 1.3 L/kg, indicating distribution into total body water; crosses placenta and enters breast milk. Stavudine: 0.5 L/kg, approximates total body water; penetrates into cerebrospinal fluid (CSF-to-plasma ratio 0.16-0.97). |
| Bioavailability | Lamivudine: oral 86-88% (tablet and solution); food delays absorption but does not reduce AUC. Stavudine: oral 86-86.4% (capsule and solution); food reduces Cmax and AUC by 30-40%. |
| Onset of Action | Lamivudine: oral, 1-2 hours to peak plasma concentration; clinical antiviral effect within 2-4 weeks. Stavudine: oral, 0.5-1.5 hours to peak plasma concentration; clinical effect within 2-4 weeks. |
| Duration of Action | Lamivudine: 12-24 hours with twice-daily dosing; intracellular active metabolite triphosphate has half-life of 10.5-15.5 hours supporting once-daily dosing. Stavudine: 8-12 hours with twice-daily dosing; intracellular active metabolite triphosphate has half-life of 3.5 hours. |
Lamivudine 150 mg plus stavudine 30 mg orally twice daily. For patients weighing ≥60 kg, stavudine 40 mg twice daily.
| Dosage form | TABLET |
| Renal impairment | For lamivudine: CrCl 30-49 mL/min: 150 mg once daily; CrCl 15-29 mL/min: 150 mg first dose then 100 mg once daily; CrCl 5-14 mL/min: 150 mg first dose then 50 mg once daily; CrCl <5 mL/min: 50 mg first dose then 25 mg once daily. For stavudine: CrCl 26-50 mL/min: 50% of usual dose; CrCl 10-25 mL/min: 25% of usual dose; CrCl <10 mL/min: data insufficient, use with caution. |
| Liver impairment | For stavudine: Child-Pugh class A or B: no adjustment; Child-Pugh class C: dose not established, use with caution. For lamivudine: no adjustment required in hepatic impairment. |
| Pediatric use | Lamivudine: 4 mg/kg (max 150 mg) twice daily; Stavudine: weight <30 kg: 1 mg/kg twice daily; weight 30-60 kg: 30 mg twice daily; weight >60 kg: adult dose. |
| Geriatric use | Use with caution due to age-related renal impairment. Monitor renal function and adjust doses accordingly based on CrCl. Start at lower end of dosing range. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Other drugs that cause peripheral neuropathy or pancreatitis increase risk Can cause peripheral neuropathy and pancreatitis.
| FDA category | Animal |
| Breastfeeding | Both lamivudine and stavudine are excreted into human breast milk. Lamivudine: M/P ratio ~3.3-6.0; infant dose ~2-8% of maternal weight-adjusted dose. Stavudine: M/P ratio unknown; present in breast milk. Breastfeeding is not recommended in HIV-infected mothers to avoid postnatal transmission of HIV. If used, monitor infant for potential adverse effects such as pancreatitis and lactic acidosis. |
| Teratogenic Risk |
■ FDA Black Box Warning
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues including lamivudine and stavudine. Stavudine in combination with didanosine is associated with a high risk of lactic acidosis and hepatotoxicity. Pancreatitis, sometimes fatal, has occurred with stavudine use.
| Common Effects | Peripheral neuropathy |
| Serious Effects |
Hypersensitivity to lamivudine or stavudine. Stavudine is contraindicated with didanosine due to increased risk of lactic acidosis and hepatotoxicity.
| Precautions | Monitor for lactic acidosis, hepatotoxicity, pancreatitis, peripheral neuropathy, lipodystrophy, immune reconstitution syndrome, and mitochondrial toxicity. Dose adjustment required for renal impairment. Coinfection with hepatitis B or C may increase risk of hepatotoxicity. |
Loading safety data…
| Lamivudine and stavudine are classified as FDA Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Animal studies have shown embryotoxicity at high doses. First trimester exposure: limited data suggest no major increase in birth defects. Second and third trimester: use primarily for maternal benefit; may reduce vertical transmission of HIV. Placental transfer occurs; both drugs cross the placenta. Risk of mitochondrial toxicity in neonates exposed in utero. |
| Fetal Monitoring | Maternal: complete blood count, liver function tests, renal function, serum lactate, and amylase at baseline and periodically; viral load and CD4+ count every 1-3 months; HIV genotype before initiation. Fetal/neonatal: growth ultrasound for potential growth restriction; HIV testing at birth, 6 weeks, and 4-6 months; monitor for signs of lactic acidosis and pancreatitis in the neonate. |
| Fertility Effects | No definitive evidence of adverse effects on fertility in humans. Animal studies have not shown impaired fertility at clinically relevant doses. HIV infection itself may affect fertility; antiretroviral therapy may improve fertility by improving health status. |